Ocular delivery systems and methods

ABSTRACT

Described here are systems and methods for accessing Schlemm&#39;s canal and for delivering an ocular device or fluid composition therein. The ocular devices may maintain the patency of Schlemm&#39;s canal without substantially interfering with transmural fluid flow across the canal. The fluid composition may be a viscoelastic fluid that is delivered into the canal to facilitate drainage of aqueous humor by disrupting the canal and surrounding trabeculocanalicular tissues. Tools for disrupting these tissues and minimally invasive methods for treating medical conditions associated with elevated intraocular pressure, including glaucoma, are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/644,758 filed on Oct. 4, 2012, which claims priority to U.S.Provisional Application Ser. No. 61/613,274 filed on Mar. 20, 2012, eachof which is hereby incorporated by reference in its entirety.

FIELD

Described here are systems and methods for accessing Schlemm's canal inan eye and for delivering an ocular device, tool or fluid compositiontherein. The ocular devices may maintain the patency of Schlemm's canalwithout substantially interfering with transmural, transluminal,circumferential, or longitudinal aqueous humor fluid flow across thecanal. The fluid composition may be a viscoelastic fluid that isdelivered into the canal to facilitate drainage of aqueous humor bydilating the canal, disrupting juxtacanalicular meshwork and theadjacent wall of Schlemm's canal, and increasing aqueous permeabilitythrough the trabeculocanalicular, or transmural, outflow pathway.Minimally invasive methods for treating medical conditions associatedwith elevated intraocular pressure, including glaucoma, are alsodescribed.

BACKGROUND

Glaucoma is a potentially blinding disease that affects over 60 millionpeople worldwide, or about 1-2% of the population. Typically, glaucomais characterized by elevated intraocular pressure. Increased pressure inthe eye can cause damage to the optic nerve which can lead to loss ofvision and even blindness if left untreated. Consistent reduction ofintraocular pressure can slow down or stop progressive loss of visionassociated with glaucoma.

Increased intraocular pressure is generally caused by sub-optimal effluxor drainage of fluid (aqueous humor) from the eye. Aqueous humor orfluid is a clear, colorless fluid that is continuously replenished inthe eye. Aqueous humor is produced by the ciliary body, and thenultimately exits the eye through the trabecular meshwork. The trabecularmeshwork extends circumferentially around the eye at the anteriorchamber angle, or drainage angle, which is formed at the intersectionbetween the peripheral iris or iris root, the anterior sclera or scleralspur and the peripheral cornea. The trabecular meshwork feeds outwardlyinto Schlemm's canal, a narrow circumferential passageway generallysurrounding the exterior border of the trabecular meshwork. Positionedaround and radially extending from Schlemm's canal are aqueous veins orcollector channels that receive drained fluid. The net drainage orefflux of aqueous humor can be reduced as a result of decreased facilityof outflow, decreased outflow through the trabecular meshwork and canalof Schlemm drainage apparatus, increased episcleral venous pressure, orpossibly, increased production of aqueous humor. Flow out of the eye canalso be restricted by blockages or constriction in the trabecularmeshwork and/or Schlemm's canal.

Glaucoma, pre-glaucoma, and ocular hypertension currently can be treatedby reducing intraocular pressure using one or more modalities, includingmedication, incisional surgery, laser surgery, cryosurgery, and otherforms of surgery. In general, medications or medical therapy are thefirst lines of therapy. If medical therapy is not sufficientlyeffective, more invasive surgical treatments may be used. For example, astandard incisional surgical procedure to reduce intraocular pressure istrabeculectomy, or filtration surgery. This procedure involves creatinga new drainage site for aqueous humor. Instead of naturally drainingthrough the trabecular meshwork, a new drainage pathway is created byremoving a portion of sclera and trabecular meshwork at the drainageangle. This creates an opening or passage between the anterior chamberand the subconjunctival space that is drained by conjunctival bloodvessels and lymphatics. The new opening may be covered with scleraand/or conjunctiva to create a new reservoir called a bleb into whichaqueous humor can drain. However, trabeculectomy carries both short andlong term risks. These risks include blockage of the surgically-createdopening through scarring or other mechanisms, hypotony or abnormally lowintraocular pressure, expulsive hemorrhage, hyphema, intraocularinfection or endophthalmitis, shallow anterior chamber angle, macularhypotony, choroidal exudation, and others. Thus, alternatives totrabeculectomy are actively being sought.

One alternative is to implant a device in Schlemm's canal that maintainsthe patency of the canal or aids flow of aqueous humor from the anteriorchamber into the canal. Various stents, shunts, catheters, andprocedures have been devised for this purpose and employ an ab-externo(from the outside of the eye) approach to deliver the implant orcatheter into Schlemm's canal. This method of placement is invasive andtypically prolonged, requiring the creation of tissue flaps and deepdissections to access the canal. Additionally, it is very difficult formany surgeons to find and access Schlemm's canal from this incisionalapproach because Schlemm's canal has a small diameter, e.g.,approximately 50 to 250 microns in cross-sectional diameter, and it maybe even smaller when collapsed. One such procedure, ab-externocanaloplasty, involves making a deep scleral incision and flap, findingand unroofing Schlemm's canal, circumnavigating all 360 degrees of thecanal with a catheter from the outside of the eye, and either employingviscoelastic, a circumferential tensioning suture, or both to helpmaintain patency of the canal. The procedure is quite challenging andcan take anywhere from forty-five minutes to two hours. The long-termsafety and efficacy of canaloplasty is very promising, but the procedureremains surgically challenging and invasive.

Another alternative to trabeculectomy is viscocanalostomy, whichinvolves the injection of a viscoelastic solution into Schlemm's canalto dilate the canal and associated collector channels. Dilation of thecanal and collector channels in this manner generally facilitatesdrainage of aqueous humor from the anterior chamber through thetrabecular meshwork and Schlemm's canal, and out through the naturaltrabeculocanalicular outflow pathway. Viscocanalostomy is similar tocanaloplasty (both are invasive and ab-externo), except thatviscocanalostomy does not involve a suture and does not restore all 360degrees of outflow facility. Some advantages of viscocanalostomy arethat sudden drops in intraocular pressure, hyphema, hypotony, and flatanterior chambers may be avoided. The risk of cataract formation andinfection may also be minimized because of the absence of full eye wallpenetration, anterior chamber opening, and iridectomy. A furtheradvantage of viscocanalostomy is that the procedure restores thephysiologic outflow pathway, thus avoiding the need for externalfiltration in the majority of eyes. This makes the success of theprocedure partly independent of conjunctival or episcleral scarring,which is a leading cause of failure in trabeculectomy. Moreover, theabsence of an elevated filtering bleb avoids related ocular discomfortand potentially devastating ocular infections, and the procedure can becarried out in any quadrant of the outflow pathway. Finally, because theentire physiology and purpose of the trabecular meshwork is unknown,retaining it may have benefits that will be realized in the future.

However, despite the advantages of viscocanalostomy and canaloplastyover trabeculectomy, current viscocanalostomy and canaloplastytechniques are still very invasive because access to Schlemm's canalmust be created by making a deep incision into the sclera and creating ascleral flap and un-roofing Schlemm's canal. In their current forms,these procedures are both “ab-externo” procedures. “Ab-externo”generally means “from the outside” and therefore inherently impliesinvasiveness. On the other hand, “ab-interno” means “from the inside”and inherently implies a less invasive or minimally invasive approach.The ab-externo viscocanalostomy and canaloplasty procedures also remainchallenging to surgeons, because as previously stated, it is difficultto find and access Schlemm's canal from the outside using a deepincisional approach due to the small diameter of Schlemm's canal. Afurther drawback still is that at most, viscocanalostomy can only dilate60 degrees of Schlemm's canal, which is a 360 degree ring-shaped outflowvessel-like structure. The more of the canal that can be dilated, themore total aqueous outflow can be restored.

Accordingly, it would be beneficial to have systems that easily andatraumatically provide access to Schlemm's canal using an ab-internoapproach for the delivery of ocular devices and compositions. It wouldalso be useful to have systems that deliver devices and compositionsinto Schlemm's canal expeditiously to decrease procedure time and therisk of infection without compromising safety and precision of thedelivery procedure. It would also be useful to have systems that deliverdevices and fluid compositions into Schlemm's canal using an ab-internoapproach so that cataract surgery and glaucoma surgery can both beaccomplished during the same surgical sitting using the very samecorneal or scleral incision. Such incisions are smaller and allow forless invasive surgery. This approach allows for accessing Schlemm'scanal through the trabecular meshwork from the inside of the eye, andthus it is called “ab-interno”. Methods of delivering ocular devices andcompositions that effectively disrupt the juxtacanalicular meshwork andadjacent wall of Schlemm's canal, also known as the inner wall ofSchlemm's canal, maintain the patency of Schlemm's canal, increaseoutflow, decrease resistance to outflow, or effectively dilate the canalusing the systems in a minimally invasive, ab-interno manner would alsobe desirable.

SUMMARY

Described here are systems and methods for easily accessing Schlemm'scanal with minimal trauma and for delivering an ocular device (e.g., animplant) therein. Other systems and methods may be implant-free, and/orrely on the delivery and removal of a therapeutic (disruptive) tooland/or the delivery of a fluid composition into Schlemm's canal toimprove flow through the trabeculocanalicular outflow system, whichconsists of the trabecular meshwork, juxtacanalicular tissue, Schlemm'scanal, and collector channels. Once implanted within the canal, theocular device may maintain the patency of Schlemm's canal withoutsubstantially interfering with transmural fluid flow across the canal.Transmural flow, or transmural aqueous humor flow, is defined as flow ofaqueous humor from the anterior chamber across the trabecular meshworkinto the lumen of Schlemm's canal, across and along the lumen ofSchlemm's canal, and ultimately into aqueous collector channelsoriginating in the outer wall of Schlemm's canal. The fluid composition,e.g., a viscoelastic fluid, delivered into the canal may facilitatedrainage of aqueous humor by dilating the canal, rendering thetrabecular meshwork and inner wall of Schlemm's canal more permeable toaqueous humor, and also dilating aqueous collector channels. Thetherapeutic tool may also facilitate drainage of aqueous humor bydilating the canal, dilating the collector channels, disrupting orstretching the trabecular meshwork, disrupting or stretching thejuxtacanalicular tissue, tearing the trabecular meshwork orjuxtacanalicular tissue, or completely removing the trabecular meshworkor juxtacanalicular tissue. Any or all of these actions may reduceresistance to outflow, increase aqueous outflow and drainage, and reduceintraocular pressure. One of the beneficial features of the system maybe a cannula configured with a distal curved portion that defines aradius of curvature, where the radius of curvature directly engages thebevel at the distal tip of the cannula. The specific configuration ofthe handle of the system may also be useful. The handle may be sized andshaped so that it is easily manipulated with one hand. Furthermore, thehandle may be designed for universal manipulation. By “universal” it ismeant that the handle is ergonomically configured for both right-handedand left-handed use, for use to access any quadrant of the eye, and foruse in advancing a cannula or conduit into Schlemm's canal in aclockwise or counterclockwise fashion. Such an ergonomic configurationmay include a drive assembly that can be actuated by fingers of one hand(e.g., the right hand) when in a first orientation, and when turned overto a second, flipped orientation, can be actuated by the fingers of theother hand (e.g., the left hand). Alternatively, the cannula itself canbe rotated to the extent needed (e.g., 180 degrees) to provideambidextrous ease of use in a clockwise or counterclockwise advancementdirection. Additionally, such a configuration may include a driveassembly that can be actuated by fingers of one hand (e.g., the righthand) to deliver an implant or fluid in a clockwise fashion when in afirst orientation, and when turned over to a second, flippedorientation, can be actuated by the fingers of the same hand (e.g., theright hand) to deliver fluid or an implant in a counterclockwisefashion.

The ocular delivery systems described herein generally include auniversal handle having a grip portion and a housing that has aninterior and a distal end. A cannula is typically coupled to and extendsfrom the housing distal end. The cannula may include a proximal end anda distal curved portion, where the distal curved portion has a proximalend and a distal end, and a radius of curvature defined between theends. The cannula may also be configured to include a body; a distal tiphaving a bevel; and a lumen extending from the proximal end through thedistal tip. The bevel may directly engage the distal end of the curvedportion of the cannula (i.e., the bevel may directly engage the radiusof curvature). The systems may also generally include a drive assemblysubstantially contained within the housing comprising gears thattranslate rotational movement to linear movement.

When an ocular device is to be implanted into Schlemm's canal, thesystem may further include a slidable positioning element having aproximal end and a distal end that is coaxially disposed within thecannula lumen. The distal end of the slidable positioning element maycomprise an engagement mechanism for positioning (includingmanipulating) the ocular device within the canal. Exemplary engagementmechanisms that may be employed comprise hooks, jaws, clasps, orcomplimentary mating elements for releasable attachment of the oculardevices.

The system may be configured to include a fluid assembly in the handleand a slidable conduit coaxially disposed within the cannula lumen whena fluid composition is to be delivered into Schlemm's canal. The fluidcomposition may be delivered through the distal end of the conduit orthrough openings spaced along the axial length of the conduit.Additionally, the fluid assembly may be coupled to a loading componentconfigured to transfer fluid compositions into a reservoir at leastpartially defined by the assembly. Some variations of the system mayhave the fluid composition preloaded in the reservoir. Exemplary fluidcompositions include without limitation, saline, pharmaceuticalcompounds, and viscoelastic fluids. The viscoelastic fluids may comprisehyaluronic acid, chondroitin sulfate, cellulose, or salts, derivatives,or mixtures thereof. Use of sodium hyaluronate as the viscoelastic fluidmay be beneficial. Additionally, commercially available syringes ofviscoelastic may be loaded into the handle to function as a reservoirwhere the plunger of the syringe is gradually compressed to deliverviscoelastic. When a therapeutic (disruptive) tool is used (without thedelivery of an implant or fluid), the handle may or may not include afluid reservoir.

Methods for implanting an ocular device within Schlemm's canal are alsodescribed. Using the ocular delivery systems disclosed herein, themethod generally includes the steps of creating an incision in theocular wall that provides access to the anterior chamber of the eye;advancing a cannula of the system through the incision, across a portionof the anterior chamber, to the trabecular meshwork, and piercing thetrabecular meshwork; accessing Schlemm's canal with the cannula; andimplanting the device within the canal. The cannula will typicallycomprise a proximal end and a distal curved portion, the distal curvedportion having a proximal end and a distal end and a radius of curvaturedefined between the ends; a body; a distal tip having a bevel, the beveldirectly engaging the distal end of the curved portion of the cannula;and a lumen extending from the proximal end through the distal tip. Apositioning element slidable within the cannula lumen may be employedduring the step of implanting the device within the canal. The devicemay be implanted to reduce intraocular pressure or to treat a medicalcondition such as glaucoma, pre-glaucoma, or ocular hypertension.

Methods for delivering a fluid composition into Schlemm's canal arefurther described. Using the ocular delivery systems disclosed herein,the method generally includes the steps of creating an incision in theocular wall that provides access to the anterior chamber of the eye;advancing a cannula of the system through the incision to the trabecularmeshwork; accessing Schlemm's canal with the cannula; and delivering thefluid composition into Schlemm's canal using a conduit slidable withinthe cannula lumen. The cannula will typically comprise a proximal endand a distal curved portion, the distal curved portion having a proximalend and a distal end and a radius of curvature defined between the ends;a body; a distal tip having a bevel, the bevel directly engaging thedistal end of the curved portion of the cannula; and a lumen extendingfrom the proximal end through the distal tip. The fluid composition maybe delivered into Schlemm's canal through the distal end of the conduitor through openings spaced along the axial length of the conduit. Fluidssuch as saline and viscoelastic solutions may be delivered into thecanal to dilate the canal and collector channels and/or to disrupt thejuxtacanalicular meshwork or inner wall of Schlemm's canal to enhancepermeability to aqueous humor, reduce resistance to aqueous outflow, orincrease aqueous outflow. Examples of viscoelastic solutions are thosethat include hyaluronic acid, chondroitin sulfate, cellulose, andderivatives and mixtures thereof. As previously stated, the use ofsodium hyaluronate as the viscoelastic solution may be beneficial. Drugsfor treating glaucoma may also be combined with the viscoelasticsolutions. The drugs may also be delivered alone without viscoelastic ifdesired.

When the fluid composition is delivered, the delivery step may includeactuation of the drive assembly so that retraction of at least a portionof the gears (or reversal of gear movement) pressurizes the reservoir inan amount sufficient to force the fluid composition through the conduitlumen. The fluid composition may be delivered to dilate Schlemm's canal.The fluid composition may also be delivered to reduce intraocularpressure or to treat a medical condition such as glaucoma.

The systems, devices, and methods described herein may also employvarying degrees of force to disrupt trabeculocanalicular tissues, e.g.,the trabecular meshwork, juxtacanalicular tissue, Schlemm's canal, wallsof Schlemm's canal, septae inside Schlemm's canal, and collectorchannels, to improve drainage of aqueous humor and in turn, reduceintraocular pressure and treat conditions of the eye. The disruptiveforce may be generated by implant-free methods, e.g., by delivering adisruptive volume of viscoelastic fluid, advancing disruptive tools,e.g., cannulas, conduits, catheters, etc., including one or moredisruptive components on their distal portions, or both. Depending onfactors such as the type or severity of the condition being treated, thedisruptive force may be generated to partially cut, tear, stretch,dilate, destroy, or completely destroy and/or remove, the trabecularmeshwork and/or juxtacanalicular tissue, and may be adjusted by varyingthe volume of viscoelastic fluid delivered, or by varying the toolconfiguration, as further discussed below.

The viscoelastic fluid may be delivered using a unitary andsingle-handed, single-operator controlled device. Advancement of thedisruptive tools may also be provided by a unitary and single-handed,single-operator controlled device. By “unitary” it is meant that onedevice is employed to advance a conduit through at least a portion ofSchlemm's canal and deliver a viscoelastic fluid, disruptive tool, orimplant into Schlemm's canal. By “single-operator controlled” it ismeant that all features of the device, e.g., cannula, conduit, and tooladvancement and retraction, ocular device delivery, fluid delivery,etc., can be performed by one user. This is in contrast to other systemsthat use forceps to advance a delivery catheter into Schlemm's canaland/or devices containing viscoelastic fluid that are separate orindependent from a delivery catheter, and which require connection tothe delivery catheter during a procedure by an assistant or assistantswhile the delivery catheter is held by the surgeon. Following deliveryof a disruptive volume of fluid or a disruptive tool, an implant, e.g.,a helical support, may be advanced into Schlemm's canal to maintain itspatency, or energy delivered to modify the structure of Schlemm's canaland/or the surrounding trabeculocanalicular tissues.

The single-handed, single-operator controlled device for deliveringfluids may include a cannula; a conduit slidably disposed within, andadvanceable distally from, the cannula; and a handle coupled to thecannula, where a portion of the handle defines a fluid reservoir, andwhere the handle is capable of being operated with a single-hand todeliver the fluid from the reservoir through the conduit.

Alternatively, a device for delivering viscoelastic fluids may include acannula; a conduit slidably disposed within, and advanceable distallyfrom, the cannula; a handle coupled to the cannula, where a portion ofthe handle defines a fluid reservoir; and a linear gear moveable toadvance a fluid from the fluid reservoir through the conduit.

The device for delivering viscoelastic fluids may also be configured toinclude a universal handle having a proximal end and a distal end; acannula extending from the distal end and having a proximal portion anda distal portion; a slidable conduit disposed within the cannula; ahousing having an interior and upper and lower surfaces; and a wheeleddrive assembly; where the wheeled drive assembly extends past the upperand lower surfaces of the housing. Such a device having a universalhandle may further include a rotating cannula that can be rotated, e.g.,from a left to right position, and a wheeled drive assembly thatcomprises a single wheel (rotatable component) configured to slide theconduit. Instead of a wheel, a button or slide could also be configuredto slide the conduit.

In all variations of the viscoelastic fluid delivery devices, theconduit may have an outer diameter ranging from about 25 microns toabout 500 microns, from about 50 microns to about 500 microns, fromabout 150 microns to about 500 microns, from about 200 microns to about500 microns, from about 300 microns to about 500 microns, from about 200microns to about 250 microns, or from about 180 microns to about 300microns. In some instances it may be beneficial for the conduit to havean outer diameter of about 240 microns. The conduit may also comprise aplurality of openings spaced along at least a portion of its axiallength or have a distal end with a cut out configured as a half tube.

In addition to disrupting Schlemm's canal and the surroundingtrabeculocanalicular tissues using a disruptive volume of viscoelasticfluid, the outer diameter of the conduit may be sized to disrupt thosetissues. For example, a conduit having an outer diameter ranging fromabout 200 microns to about 500 microns may be beneficial for disruptingtissues. Furthermore, a distal portion of the conduit may include adisruptive component, e.g., a notch, hook, barb, or combinationsthereof, that disrupts tissues. However, the devices may not need toinclude both features, i.e., deliver a disruptive volume of viscoelasticfluid and also have a conduit sized for disruption. A conduit sized orconfigured for disruption of Schlemm's canal and surrounding tissues maybe used alone to reduce intraocular pressure, without the delivery offluids. Such a conduit may or may not have a lumen. Conduits may also beconfigured to be inflatable or expandable to a size that disruptstissues as it is advanced.

The handle of the viscoelastic fluid delivery devices described hereinmay include a drive assembly capable of pressurizing the fluid todeliver the fluid from the reservoir through the conduit. The driveassembly may be a wheeled drive assembly that includes one rotatablecomponent or a plurality of rotatable components. The reservoir may bepreloaded with the viscoelastic fluid. Exemplary viscoelastic fluids maycomprise hyaluronic acid, chondroitin sulfate, cellulose, or salts,derivatives, or mixtures thereof. It may be beneficial to use sodiumhyaluronate as the viscoelastic fluid.

The implant-free methods for treating conditions of the eye may includeadvancing a conduit into Schlemm's canal, where the conduit has beenloaded with a volume of viscoelastic fluid, and delivering theviscoelastic fluid into Schlemm's canal at a volume sufficient todisrupt the trabeculocanalicular tissues to reduce intraocular pressure.However, the implant-free methods for treating conditions of the eye maynot necessarily include delivery of viscoelastic fluids. In theseinstances, the method may comprise advancing a device into Schlemm'scanal, where the device has a diameter between about 200 and about 500microns, and where advancement of the device into Schlemm's canaldisrupts the trabeculocanalicular tissues sufficient to reduceintraocular pressure.

Other methods for treating conditions of the eye may be single-handed,single-operator methods for introducing viscoelastic fluid intoSchlemm's canal that include advancing a conduit into Schlemm's canal,where the conduit has been loaded with a volume of viscoelastic fluid,and delivering the viscoelastic fluid into Schlemm's canal, wheredelivering the volume of viscoelastic fluid is accomplished by asingle-handed device used by a single operator.

When viscoelastic fluids are delivered in the methods disclosed herein,the disruptive volume may be between about 2 μl (microliters) to about16 μl (microliters), or between about 2 μl to about 8 μl. In somevariations of the method, the volume of fluid capable of disruptingtrabeculocanalicular tissues is about 2 μl, about 3 μl, about 4 μl,about 5 μl, about 6 μl, about 7 μl, about 8 μl, about 9 μl, about 10 μl,about 11 μl, about 12 μl, 13 μl, about 14 μl, about 15 μl, or about 16μl. It may be beneficial to deliver a volume of about 4 μl ofviscoelastic fluid in certain instances. In yet further variations, thevolume of fluid delivered ranges from about 1 μl per 360 degrees of thecanal to about 50 μl per 360 degrees of the canal. The viscoelasticfluid may be delivered while advancing the conduit of a single-handed,single-operator controlled device from Schlemm's canal in the clockwisedirection, counterclockwise direction, or both, and/or during withdrawalof the conduit from Schlemm's canal. As previously stated, theviscoelastic fluid may be delivered to disrupt Schlemm's canal andsurrounding trabeculocanalicular tissues. For example, the deliveredviscoelastic fluid may cause disruption by dilating Schlemm's canal,increasing the porosity of the trabecular meshwork, stretching thetrabecular meshwork, forming microtears in juxtacanalicular tissue,removing septae from Schlemm's canal, dilating collector channels, or acombination thereof. The conduit may be loaded with the viscoelasticfluid at the start of an ocular procedure so that a single-operator canuse a single hand to manipulate the device (e.g., advance and retractthe conduit or any associated tool) and deliver the fluid into thetrabeculocanalicular tissues.

The methods disclosed herein may also include advancement of the conduitabout a 360 degree arc of Schlemm's canal, a 180 degree arc of Schlemm'scanal, or a 90 degree arc of Schlemm's canal. Advancement may occur froma single access point in Schlemm's canal or from multiple access pointsin the canal. The disclosed methods may also be used to treat a varietyof eye conditions, including, but not limited to, glaucoma,pre-glaucoma, and ocular hypertension.

Methods for ab-interno trabeculotomy and goniotomy are also disclosedusing the devices and steps disclosed herein, including advancing acannula at least partially through the anterior chamber of the eye,entering Schlemm's canal at a single access point using the cannula, anddelivering a volume of a viscoelastic fluid through a conduit slidablewithin, and extendable from, the cannula, sufficient to disrupt thestructure of Schlemm's canal and surrounding trabeculocanaliculartissues to reduce intraocular pressure. Another method that may beuseful in treating conditions of the eye includes entering Schlemm'scanal using a conduit extendable from a single-operator controlledhandle, the handle comprising a fluid reservoir, and delivering a volumeof a viscoelastic fluid from the fluid reservoir through the conduit byincreasing pressure within the fluid reservoir, where the volume ofdelivered viscoelastic fluid is sufficient to disrupt the structure ofSchlemm's canal and surrounding tissues to reduce intraocular pressure.Other methods for ab-interno trabeculotomy and goniotomy may includecutting, tearing, and/or removing trabecular meshwork without thedelivery of a viscoelastic fluid. In such methods, a conduit configuredto mechanically tear and remove trabecular meshwork may be employed.Here the conduit may comprise a larger diameter, cutting features,and/or tool along or at the distal portion or the conduit. For example,if the trabecular meshwork were being both cut and removed, the conduitmight pull excised tissue back into the cannula during retraction.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a stylized, cross-sectional view of the eye and some of thestructures involved in the flow of aqueous humor out of the eye.

FIG. 2 depicts a perspective view of an exemplary delivery system forimplanting an ocular device.

FIG. 3 depicts a side view of an exemplary cannula of the deliverysystem.

FIGS. 4A-4B depict perspective views of an exemplary drive assembly.FIG. 4A shows the drive assembly in the handle of the system in a firstorientation for use with one hand and FIG. 4B shows the handle in asecond, flipped orientation that can be used with the other hand.

FIGS. 5A-5B show perspective views of an exemplary engagement mechanism.

FIG. 6 shows a perspective view of an engagement mechanism according toone variation.

FIGS. 7A-7B show perspective views of engagement mechanisms according toother variations.

FIG. 8A-8B depict perspective views of an engagement mechanism accordingto yet a further variation.

FIG. 9 depicts a perspective view of another exemplary engagementmechanism.

FIGS. 10A-10B show an exemplary delivery system for delivering a fluidcomposition into Schlemm's canal. FIG. 10A is a perspective view of thesystem. FIG. 10B is a partial cross-sectional view of the system.

FIGS. 11A-11C illustrate an exemplary method of delivering a fluidcomposition out of the delivery system.

FIG. 12 depicts an exemplary slidable conduit for delivering a fluidcomposition.

FIGS. 13A-13C show side or perspective views of slidable conduitsaccording to other variations.

FIG. 14 is a stylized depiction of an ab-interno method for accessingSchlemm's canal with the cannula of an exemplary delivery system.

FIG. 15 depicts an exemplary cannula according to another variation.

FIG. 16 is a stylized depiction of an ab-interno method of accessingSchlemm's canal from a single point, and delivering a viscoelastic fluidwhile advancing a fluid delivery conduit along a 360 degree arc of thecanal.

FIG. 17 is a stylized depiction of an ab-interno method of accessingSchlemm's canal from a single point, and delivering a viscoelastic fluidwhile advancing a fluid delivery conduit in both the clockwise andcounterclockwise directions along a 180 degree arc of the canal.

FIGS. 18A-18C illustrate an exemplary ab-interno method of cutting ortearing the trabecular meshwork.

DETAILED DESCRIPTION

Described here are systems and methods for accessing Schlemm's canal andfor delivering an ocular device and/or fluid composition therein toreduce intraocular pressure and thereby treat conditions of the eye. Thefluids and certain components of the system, e.g., the slidable conduit,may be used to provide a force for disrupting trabeculocanaliculartissues, which include the trabecular meshwork, juxtacanalicular tissue,Schlemm's canal, and the collector channels. As used herein, the term“disrupting” refers to the delivery of a volume of fluid or a systemcomponent that alters the tissue in a manner that improves flow throughthe trabeculocanalicular outflow pathway. Examples of tissue disruptioninclude, but are not limited to, dilation of Schlemm's canal, dilationof collector channels, increasing the porosity of the trabecularmeshwork, stretching the trabecular meshwork, forming microtears injuxtacanalicular tissue, removing septae from Schlemm's canal, cuttingor removal of trabeculocanalicular tissues, or a combination thereof.

To better understand the systems and methods described here, it may beuseful to explain some of the basic eye anatomy. FIG. 1 is a stylizeddepiction of a normal human eye. The anterior chamber (100) is shown asbounded on its anterior surface by the cornea (102). The cornea (102) isconnected on its periphery to the sclera (104), which is a tough fibroustissue forming the white shell of the eye. Trabecular meshwork (106) islocated on the outer periphery of the anterior chamber (100). Thetrabecular meshwork (106) extends 360 degrees circumferentially aroundthe anterior chamber (100). Located on the outer peripheral surface ofthe trabecular meshwork (106) is Schlemm's canal (108). Schlemm's canal(108) extends 360 degrees circumferentially around the meshwork (106).At the apex formed between the iris (110), meshwork (106), and sclera(104), is angle (112).

The systems are generally configured for single-handed manipulation andfor control by a single operator, and include one or more featuresuseful for easily accessing Schlemm's canal with minimal trauma. Onceaccess to the canal has been obtained, the system may deliver an oculardevice, a fluid composition, or both. In some variations, the systemadvances a tool that disrupts Schlemm's canal and surrounding tissueswithout delivery of an ocular device or a fluid composition. Forexample, the tool may be a conduit, slidable within, and extendablefrom, the cannula used to access the canal, having an outer diametersized to disrupt the canal and surrounding tissues. The distal end ofthe conduit may also be provided with a disruptive component to aid inthe disruption of trabeculocanalicular tissues.

The device that is implanted into the canal will generally be configuredto maintain the patency of Schlemm's canal without substantiallyinterfering with transmural fluid flow across the canal. Ocular implantssuch as those disclosed in U.S. Pat. No. 7,909,789 may be delivered. Insome variations, the implants in U.S. Pat. No. 7,909,789 include asupport having a least one fenestration that completely traverses acentral core of Schlemm's canal without substantially interfering withtransmural fluid flow or longitudinal fluid flow across or along thecanal. The ocular device may also disrupt the juxtacanaliculartrabecular meshwork or adjacent inner wall of Schlemm's canal. Theocular devices may also be coated with a drug useful for treating ocularhypertension, glaucoma, or pre-glaucoma, infection, or scarring orinflammation postoperatively. The ocular device may also be formed to besolid, semi-solid, or bioabsorbable.

The systems may also be used to deliver a fluid composition, e.g.,saline or a viscoelastic fluid. The saline may be used for irrigation.The viscoelastic fluid may be employed in ab-interno versions ofviscocanalostomy or canaloplasty procedures to disrupt the canal andsurrounding tissues.

I. Systems/Devices

The systems described herein may be single-handed, single-operatorcontrolled devices that generally include a universal handle having agrip portion and a housing that has an interior and a distal end. Acannula is typically coupled to and extends from the housing distal end.The cannula may include a proximal end and a distal curved portion,where the distal curved portion has a proximal end and a distal end, anda radius of curvature defined between the ends. The cannula may also beconfigured to include a body; a distal tip having a bevel; and a lumenextending from the proximal end through the distal tip. The bevel maydirectly engage the distal end of the curved portion of the cannula(i.e., the bevel may directly engage the radius of curvature). Thesystems may also generally include a drive assembly partially containedwithin the housing comprising gears that translate rotational movementto linear movement. When an ocular device is to be implanted intoSchlemm's canal, the systems may further include a slidable positioningelement having a proximal end and a distal end that is coaxiallydisposed within the cannula lumen. The system may also be configured toinclude a fluid assembly in the handle and a slidable conduit coaxiallydisposed within the cannula lumen when a fluid composition is to bedelivered into Schlemm's canal. Fluid compositions such as saline,viscoelastic fluids, including viscoelastic solutions, air, and gas maybe delivered using the system. Suitable markings, colorings, orindicators may be included on any portion of the system to help identifythe location or position of the distal end of the cannula, thepositioning element, the engagement mechanism, the ocular device, or theslidable conduit.

Universal Handle

The ocular delivery systems described herein may include a universalhandle capable of single-handed use. For example, the handle may beconfigured to be capable for use with the right hand in one orientation,and then with a simple flip of the handle (or by rotating the cannulaitself 180 degrees) to a second orientation, use with the left hand. Thehandle generally includes a grip portion and a housing. The grip portionmay be raised, depressed, or grooved in certain areas, or textured toimprove hold of the handle by the user or to improve comfort of theuser. The housing may include an interior portion and a distal end. Theinterior portion of the housing may contain a drive assembly and apositioning element (both further described below). In some variations,the distal end of the housing includes a fluid port that can providefluids for irrigation of the operative field or to purge air from thesystem.

The universal handle may be made from any suitable material, includingwithout limitation, fluoropolymers; thermoplastics such aspolyetheretherketone, polyethylene, polyethylene terephthalate,polyurethane, nylon, and the like; and silicone. In some variations, thehousing or portions thereof may be made from transparent materials.Materials with suitable transparency are typically polymers such asacrylic copolymers, acrylonitrile butadiene styrene (ABS),polycarbonate, polystyrene, polyvinyl chloride (PVC), polyethyleneterephthalate glycol (PETG), and styrene acrylonitrile (SAN). Acryliccopolymers that may be particular useful include, but are not limitedto, polymethyl methacrylate (PMMA) copolymer and styrene methylmethacrylate (SMMA) copolymer (e.g., Zylar 631® acrylic copolymer).

The length of the universal handle may generally be between about 4inches (10.2 cm) and 10 inches (25.4 cm). In some variations, the lengthof the universal handle is about 7 inches (17.8 cm).

Cannula

The cannula of the ocular delivery system is typically coupled to andextends from the housing distal end, and is generally configured toprovide easy and minimally traumatic access to Schlemm's canal using aminimally invasive ab-interno approach. Some variations of the cannulamay include a proximal end and a distal curved portion, where the distalcurved portion has a proximal end and a distal end, and a radius ofcurvature defined between the ends. The cannula may also be configuredto include a body; a distal tip having a bevel; and a lumen extendingfrom the proximal end through the distal tip. The bevel may directlyengage the distal end of the curved portion of the cannula (i.e., thebevel may directly engage the radius of curvature).

The cannula may be made from any suitable material with sufficientstiffness to allow it to be advanced through the eye wall and anteriorchamber. For example, the cannula may be formed of a metal such asstainless steel, nickel, titanium, aluminum, or alloys thereof (e.g.,Nitinol® metal alloy) or a polymer. Exemplary polymers include withoutlimitation, polycarbonate, polyetheretherketone (PEEK), polyethylene,polypropylene, polyimide, polyamide, polysulfone, polyether block amide(PEBAX), and fluoropolymers. In some instances, it may be advantageousto coat the cannula with a lubricious polymer to reduce friction betweenthe ocular tissue and the cannula during the procedure. Lubriciouspolymers are well known in the art, and include, without limitation,polyvinyl alcohol, polyethylene glycol, polyvinyl pyrrolidone,fluorinated polymers (including polytetrafluoroethylene (PTFE orTeflon®)), and polyethylene oxide.

The cannula generally has an outer diameter sized to gain access to thelumen of Schlemm's canal while minimally obstructing the surgeon's view.Accordingly, the outer diameter may range from about 150 microns toabout 800 microns. The cannula also has an inner diameter, which mayrange from about 50 microns to about 400 microns. The cannula may alsobe formed to have any suitable cross-sectional profile, e.g., circular,elliptical, triangular, square, rectangular, etc.

The cannula may be configured to include multiple portions or parts. Acannula having a body, a distal curved portion having a proximal end anda distal end, a radius of curvature defined between the ends, and abevel at the distal tip of the cannula that directly engages the distalend of the curved portion of the cannula may be particularly useful foraccessing the lumen of Schlemm's canal. Here the body (straight portionof the cannula) may have a length ranging from about 5 mm to about 50mm, about 10 mm to about 30 mm, or from about 14 mm to about 20 mm. Insome variations, the body may have a length of about 18 mm. The distalcurved portion of the cannula may be uniform in cross-sectional shape orit may taper closer to the distal end to facilitate entry into Schlemm'scanal. The radius of curvature of the distal curved portion may beadapted to facilitate tangential entry, as well as precise and minimallytraumatic entry into Schlemm's canal, and may range from about 1 mm toabout 10 mm or from about 2 mm to about 5 mm. In one variation, theradius of curvature is about 2.5 mm. The cannula may also have anangular span suitable for facilitating entry into Schlemm's canal, andmay range from about 70 degrees to about 170 degrees, or about 100degrees to about 150 degrees. In one variation, the angular span isabout 120 degrees.

The size, shape, geometry, etc., of the bevel at the distal end of thecurved portion of the cannula may be beneficial in allowing easy andminimally traumatic access to Schlemm's canal. In this respect, and asdescribed in further detail below, having a bevel that directly engagesthe radius of curvature of the distal end of the cannula may beparticularly useful.

In other variations, the cannula may include a short straight segmentcoupled to the distal end of the distal curved portion of the cannula(e.g., at the end of the radius of curvature). Here the bevel engagesthe straight segment and not the radius of curvature. The length of thestraight segment may range from about 0.5 mm to about 5 mm. In somevariations, the length of the straight segment ranges from about 0.5 mmto about 3 mm, or from about 0.5 mm to about 1 mm. The length of thestraight segment may also less than about 0.5 mm, e.g., it may be about0.1 mm, about 0.2 mm, about 0.3 mm, or about 0.4 mm. In variations wherethe bevel directly engages the distal end of the curved portion of thecannula (i.e., the bevel directly engages the radius of curvature), thecannula lacks a straight segment (length of the straight segment iszero).

It may also be useful to have a bevel that is sharp and short tominimize the distance that any ocular device will have to travel whenbeing implanted into the canal. Exemplary bevel angles may range fromabout 10 degrees to about 90 degrees. In one variation, the bevel angleis about 35 degrees. The bevel may also be oriented in suitabledirection. For example, the bevel may be oriented so that it opens uptowards the surgeon, or it may be reversed to open away from the surgeonor in any plane in between.

In yet further variations, the cannula is configured to include onesection that is sharp, and another section that is blunt (e.g.,deburred). The dual surface configuration of such a cannula may beadvantageous since it may provide easier canal access by piercing themeshwork while also providing a gentle, dispersed force on the conduitduring conduit retraction into the cannula to avoid cutting or breakingthe conduit due to retraction force. For example, as shown in FIG. 15,the distal end of cannula (1500) may have a sharp, piercing tip (1502)and a smooth edge (1504) that define portions of opening (1506), throughwhich 1600 a slidable conduit (not shown) may be advanced and retracted.The sharp tip (1502) may be formed by compounding multiple bevels. Thesmooth edge (1504) may be created by laser ablation or deburring aninner bevel edge.

Drive Assembly

The drive assembly of the delivery system is generally configured tomove an ocular device, conduit, and/or fluid composition out of theuniversal handle and into Schlemm's canal. The drive assembly may alsobe configured to position an ocular device within the canal, includingadvancing the device into the canal and retracting the device from thecanal. The drive assembly may be at least partially contained within thehousing and may include any suitable component or combination ofcomponents capable of providing the handle with universal functionality.In some variations, the drive assembly includes components thattranslate rotational motion into linear motion. For example, the driveassembly may include a linear gear and a pair of pinion gear mechanisms.The linear gear may have teeth on its surface that engage correspondingteeth on the pinion gears. Each of the pinion gear mechanisms may alsobe coupled to a rotatable component (e.g., a wheel). Such coupling maybe accomplished with a pin that can be threaded through a centralopening in the rotatable component and pinion gear, and a nut thatsecures the rotatable component and pinion gear in a manner so thatrotation of the rotatable component also rotates the pinion gear andvice versa. The wheels may be attached to the pinion gear by one of thefollowing methods: 1) the wheels and pinion gears are molded as one partusing plastic injection molding technology; 2) the wheels slide onto thepinion gear and secured with adhesive; or 3) the wheels slide on thepinion gear and are mechanically fixed with a fastener or a “press fit”,where the wheels are forced onto the pinion gear and friction holds themsecure. In all of the mentioned situations, the wheels and pinion gearsmay rotate coaxially, in the same direction, and at the same angularrate. In some variations, each of the pinion gear mechanisms is coupledto at least two rotatable components. In other variations, the driveassembly may be configured to include a single rotatable component, aplurality of rotatable components, or no rotatable component. The wheelmay have markings or colorings to indicate degree of advancement ordirection of advancement.

One variation of the drive assembly useful to include in the universalhandle comprises a linear gear, a pair of pinion gear mechanisms, andtwo rotatable components coupled to each pinion gear (for a total offour rotatable components). Here the pinion gear mechanisms andassociated wheels would be disposed on either side of the linear gear.The pinion gears and linear gear would contact each other, i.e., theteeth of the pinion gears would directly engage corresponding teeth onthe linear gear, and the wheels on one side of the linear gear wouldcontact the wheels on the opposite side of the linear gear. In thisvariation, the drive assembly can be manipulated with one hand when in afirst configuration, and then manipulated with the other hand whenflipped over to a second configuration. A drive assembly having suchflexible capability can be easily used by a surgeon who is right handdominant or left hand dominant. In a further variation, the driveassembly may include one rotatable component on one side of the handleand the “universal” feature of the handle provided by a cannula thatitself can rotate instead of flipping the handle.

One or both pinion gear mechanisms can be disengaged from the lineargear by biasing their position off axis from the linear gear. Thisaction de-couples the pinion gear teeth to the linear gear teeth toprevent linear gear movement. The pinion gear mechanism can also belocked to prevent rotation by engaging an intersecting pin or featurethat prevents wheel rotation.

In other variations, the drive assembly includes a linear gear and asingle pinion gear mechanism with two associated wheels. Furthervariations of the drive assembly may not employ translation ofrotational motion to linear motion. For example, a slide (e.g., a fingerslide) on the handle that is fixed or detachably coupled to a gearwithin the housing of the handle (e.g., a linear gear as previouslydescribed) could be used to deliver an ocular device or fluidcomposition. Here the drive assembly may be configured so thatadvancement of the slide correspondingly advances components thatdeliver an ocular device or fluid composition into Schlemm's canal, andretraction of the slide correspondingly retracts those components. Inyet further variations, a button that can be pressed by one finger orsqueezed by two fingers could be employed instead of a slide.

Positioning Element

The ocular delivery systems may further include a slidable positioningelement coaxially disposed within the lumen of the cannula forcontrolled implantation of an ocular device within Schlemm's canal. Thepositioning element generally comprises a proximal end, a distal end,and an engagement mechanism at the distal end. The ocular device isgenerally releasably coupled to the engagement mechanism. Thepositioning element may be advanced to deploy an ocular device withinthe cannula into Schlemm's canal, or it may be retracted to help withpositioning and/or repositioning of an ocular device, or disengagementof an ocular device from the engagement mechanism.

Some variations of the engagement mechanism include a proximal coiledportion and a distal hook. When an implant having at least onefenestration (e.g., a proximal fenestration) is to be implanted, thehook may be releasably engaged to the fenestration. The ocular devicemay be disengaged from the hook by the application of gentle force onthe coil or by another component that can be advanced over the coil topush the device off the hook or by using shape memory materials thatpassively disengages when exiting the cannula. It may be advantageous touse the hook when retraction of the ocular device is desired. Thesurgeon may simply move the delivery system and engagement mechanism sothat it disengages any fenestration or notch on the implant.

In another variation, the engagement mechanism includes opposing jaws.Here the engagement mechanism may include a first jaw and a second jaw,where the jaws have a closed configuration and an open configuration.The jaws may be used to grip and manipulate the ocular device, andreleasably couple the ocular device to the positioning element. The jawsmay be formed by splitting or bifurcating the distal end of a wire,e.g., by laser cutting. The grasping force of the jaws may be achievedby constraining the jaws within the cannula. The ocular device may bereleased once the jaws are advanced out of the cannula and expand. Thejaws may also be pivotably connected. In yet another variation, thefirst jaw may include at least one tine, and the second jaw may includeat least one aperture for receiving the tine when the jaws are in theclosed configuration.

In further variations, the engagement mechanism comprises a loopedportion. This variation of the engagement mechanism will typically beused with an ocular device comprising a spring-like clasp at itsproximal end, where the clasp has a collapsed configuration and anexpanded configuration. The clasp is generally fabricated in theexpanded position. Thus, when a device having a clasp is disposed withinthe cannula, the first and second arms or tabs of the clasp may collapsearound the looped portion of the engagement mechanism. Once the claspedportion of the device has exited the cannula, the arms or tabs mayexpand to release the ocular device from the looped portion.

Still another variation of the engagement mechanism includes a female tomale interface. For example, the engagement mechanism may comprise anotch configured to interface with a complimentary mating element (e.g.,a tab) on the ocular device. The notch (female component) may be formedwithin hypodermic tubing or may be made by creating a fenestrationthrough the distal end of a positioning element made from a solid wireor element, and the tab or hook (male component) may formed as part ofthe ocular device and may be inserted into the fenestration or notch inthe positioning element. With this configuration, the ocular device maybe released from the positioning element as it is advanced out of thecannula either by the surgeon's manipulation or by shape setting of thepositioning element that causes it to passively detach from the oculardevice or both.

Reservoir and Slidable Conduit

The systems generally include a reservoir when a fluid composition is tobe delivered into Schlemm's canal. As further described below, thereservoir may be at least partially defined by a fluid assembly and thehousing, and the linear gear within the handle. The fluid assembly maybe made from any suitable material previously mentioned for the cannulaand the housing. The volume of fluid (in microliters) contained withinthe reservoir may range from about 2 μl to about 1000 μl, or from about2 μl to about 500 μl. In some variations, the reservoir volume may rangefrom about 50 μl to about 100 μl. Some variations of the fluid assemblyinclude a locking mechanism for preventing movement of the assemblywithin the handle, e.g., when the linear gear is being advanced orretracted. The locking mechanism may comprise a ratchet pawl, acombination of ratchet pawls or any other suitable mechanism that can belocked to prevent movement of the fluid assembly, and unlocked to allowmovement of the fluid assembly.

The fluid composition may be preloaded in the reservoir or loaded intothe reservoir prior to use of the system, e.g., at the start of anocular procedure, so that the fluid can be delivered by a single deviceand by a single user. Again, this is in contrast to other systems thatuse forceps or other advancement tools to advance a fluid deliverycatheter into Schlemm's canal and/or devices containing viscoelasticfluid that are separate or independent from a delivery catheter orcatheter advancement tool, and which require connection to the deliverycatheter or catheter advancement tool during a procedure by, e.g., anassistant, or by the hand of the surgeon while the delivery catheter orcatheter advancement tool is held by another hand of the surgeon. Forexample, a loading component may be provided on the fluid assembly fortransfer of a fluid composition into the reservoir. The loadingcomponent may have any suitable configuration that provides reversiblesecurement of a fluid container, e.g., a syringe, cartridge, etc., tothe system, and loading of a fluid composition into the reservoir. Theloading component may be a luer fitting or include a one-way valve. Aslidable conduit coaxially disposed within the cannula lumen may beoperatively connected to the reservoir for delivery of a fluidcomposition into Schlemm's canal. The slidable conduit generally has aproximal end, a distal end, and a wall that defines a conduit lumenextending therethrough. However, in some instances, the delivery systemlacks a slidable conduit, and the fluid composition is delivered solelythrough the cannula. In other instances, two slidable conduits may beemployed that each simultaneously advance through the canal in bothclockwise and counterclockwise directions to more rapidly cannulateSchlemm's canal and deliver therapy. As previously stated, the fluid maybe delivered in a volume that provides sufficient force to disruptSchlemm's canal and surrounding trabeculocanalicular tissues. Exemplarydisruptive volumes may be about 1 μl, about 2 μl, about 3 μl, about 4μl, about 5 μl, about 6 μl, about 7 μl, about 8 μl, about 9 μl, about 10μl, about 11 μl, about 12 μl, about 13 μl, about 14 μl, about 15 μl,about 16 μl, about 17 μl, about 18 μl, about 19 μl, or about 20 μl. Insome variations, the disruptive volume fluid may range from about 1 μlto about 50 μl, or from about 20 μl to about 50 μl.

The slidable conduit may be made from any suitable material that impartsthe desired flexibility and pushability for introduction through the eyewall, accessing Schlemm's canal, and/or navigation through other oculartissue structures. For example, the conduit may comprise a polymer; apolymer reinforced with metal wire, braid or coil; composites ofpolymers and metal; or metals such as stainless steel, titanium,nitinol, or alloys thereof. The slidable conduit may be straight withenough flexibility and pushability to navigate the ring-shaped Schlemm'scanal or may be pre-shaped to about a 2-10 mm radius of curvature orabout a 6 mm radius of curvature (i.e. the approximate radius ofcurvature of Schlemm's canal in an adult human) to more easilycircumnavigate Schlemm's canal, partially or in its entirety. In someother variations, the slidable conduit includes a plurality of openingsthrough its wall that are spaced along the axial length of the conduit.In this variation, the fluid composition may be delivered from thereservoir through the openings in the conduit and into Schlemm's canal.This lateral ejection of fluid (e.g., a viscoelastic fluid) wouldfurther enhance disruption of outflow tissues and enhance permeabilityto aqueous humor. It is understood that the openings can be of anysuitable number, size and shape, and spaced along the axial length ofthe conduit (including the distal end) in any suitable manner. In othervariations, the distal end of the slidable conduit may be configured ormodified to aid delivery of the fluid composition into Schlemm's canal.For example, the distal end of the conduit may comprise a cut outconfigured as a half tube. The distal end of the conduit may also beconfigured as a blunt bevel, an atraumatic tip, an enlarged atraumatictip, or a rough surface that disrupts the juxtatrabecular portion ofSchlemm's canal or juxtatrabecular meshwork. Additionally, the conduitmay have one or more projections emanating from it to further disruptthe juxtatrabecular portion of Schlemm's canal or juxtatrabecularmeshwork and thus increase permeability of aqueous humor through thetrabecular meshwork into Schlemm's canal. In some instances, the conduitmay also deliver energy to the trabeculocanalicular tissues. In otherinstances, the conduit may be an off the shelf commercially available orcustomized polypropylene suture (or other material). The suture may besized so that it can be advanced through the cannula and into a portionof Schlemm's canal (e.g., 0 to 360 degrees of the canal) to disrupt,stent, and/or apply tension to the canal, and/or to tear thetrabeculocanalicular tissues. An exemplary range of suture size mayrange from about 50 microns to about 300 microns. The suture may beremoved from the canal or left within the canal to continuously delivertension on the meshwork and maintain patency of the canal.

The cannula of the systems described herein may also deliver varioussurgical tools by ab-interno methods. For example, catheters, wires,probes, and other tools may also be employed ab-interno to accessSchlemm's canal and then to create holes, partial thickness disruptions,or perforations in discreet locations or all along the trabecularmeshwork or inner wall of Schlemm's canal. The surgeon may also advancethe tools all the way across the canal and through the collector channelouter wall to access the sclera and subconjunctival space (again allfrom an ab-interno approach) to make incisions that create a sclerallake into which aqueous can drain to the scleral veins orsubconjunctival space or to deliver an ocular device ab-interno thatresides and drains into the scleral lake or sub conjunctival space fromthe anterior chamber or Schlemm's canal.

The reservoir may contain various fluid compositions for delivery intoSchlemm's canal. Exemplary fluid compositions include saline andviscoelastic fluids. The viscoelastic fluids may comprise hyaluronicacid, chondroitin sulfate, cellulose, derivatives or mixtures thereof,or solutions thereof. In one variation, the viscoelastic fluid comprisessodium hyaluronate. In another variation, the viscoelastic compositionmay further include a drug. For example, the viscoelastic compositionmay include a drug suitable for treating glaucoma, reducing or loweringintraocular pressure, reducing inflammation, and/or preventinginfection. Drugs such as an antimetabolite, steroid, heparin, otheranticoagulants, and fibrinolytic compounds may also be delivered incombination with the viscoelastic composition. Examples of glaucomadrugs include prostaglandins, beta blockers, miotics, alpha adrenergicagonists, or carbonic anhydrase inhibitors. Anti-inflammatory drugs suchas corticosteroids or other steroids may be used. For example, steroidssuch as prednisolone, prednisone, cortisone, cortisol, triamcinolone, orshorter acting steroids may be employed. Examples of antimetabolitesinclude 5-fluoruracil or mitomycin C. In still another variation, thesystem delivers the drug alone, without the viscoelastic composition.Saline solution may also be the fluid employed.

In other variations, the devices/systems may include a slidable conduitthat does not deliver a fluid, but which is sized to have an outerdiameter sufficient to disrupt Schlemm's canal and surroundingtrabeculocanalicular tissues. The outer diameter may range from about 50microns to about 500 microns, from about 300 microns to about 500microns, from about 200 microns to about 250 microns, or from about 180microns to about 300 microns. In some instances it may be beneficial forthe conduit to have an outer diameter of about 240 microns. Furthermore,a distal portion of the conduit may include a disruptive component,e.g., a notch, hook, barb, or combination thereof, to disrupt tissues.

An exemplary ocular delivery system is depicted in FIG. 2. In thefigure, delivery system (200) includes a universal handle (202) having agrip portion (204) and a housing (206). The housing has a proximal end(208) and a distal end (210). A cannula (212) is coupled to and extendsfrom the housing distal end (210). A drive assembly (214) issubstantially contained within the housing (206) that actuates movementof a positioning element (not shown). Port (216) is provided on thedistal end of the housing (210) for removable connection to a source ofirrigation fluid.

The cannula of an exemplary delivery system is shown in more detail inFIG. 3. Here the cannula (300) comprises a proximal end (302) a distalcurved portion (304), a body (314), and a distal tip (306). The distalcurved portion (304) has a proximal end (308) and a distal end (310),and a radius of curvature (R) that is defined between the ends (308,310). A bevel (312) at the distal tip (306) directly engages the distalend of the curved portion of the cannula (310). In other words, thebevel (312) may be contiguous with the distal end of the curved portionof the cannula (310). As previously stated, this configuration of thedistal curved portion (304) and bevel (312) may be beneficial oradvantageous for allowing easy, atraumatic, and controlled access intoSchlemm's canal. The angle of the bevel may also be important. Ingeneral, a short bevel may be beneficial. Here the bevel angle (A) isabout 35 degrees.

The ocular delivery systems generally include a drive assemblysubstantially contained within the housing. In the variation shown inFIG. 4A, delivery system (400) includes a drive assembly (402) having alinear gear (e.g., a rack) (404) and a pair of pinion gear mechanisms(406). Both the linear gear and the pinion gear mechanisms have teeththat engage each other to translate rotational motion (of the piniongear mechanisms 406) to linear motion (of the linear gear 404). Each ofthe pinion gear mechanisms (406) are coupled to two rotatablecomponents, shown in the figure as wheels (408), for a total of fourrotatable components. The wheels (408) may be rotated by one or more ofthe surgeon's fingers to correspondingly rotate the pinion gearmechanism (406) and thus advance or retract the linear gear (404). Thewheels (408) are coaxial with the pinion gear mechanism (406) and rotatein unison with the pinion gear mechanism. Movement of the linear gear(404) advances or retracts a positioning element (410) that is coaxiallydisposed and slidable within cannula (412). FIG. 4B shows the system ofFIG. 4A in a second, flipped orientation that can be used with theopposite hand (e.g., by the left hand if the system of FIG. 4A was usedwith the right hand), or that can be used by the same hand, but adifferent direction of cannulation is desired (e.g., clockwisecannulation if counterclockwise cannulation was performed with thesystem in FIG. 4A).

When the delivery system is used to implant an ocular device, thecannula may have a slidable positioning element coaxially disposedwithin the cannula lumen. The slidable positioning elements generallyinclude an engagement mechanism for manipulating, e.g., releasablyengaging, advancing and/or retracting, an ocular device. Exemplaryengagement mechanisms are depicted in FIGS. 5-9.

In FIG. 5A, the engagement mechanism (500) comprises a first jaw (502)and a second jaw (504). In their closed configuration (as shown in FIG.5A), the jaws (502, 504) are constrained within cannula (512) and holdan ocular device (506) comprising a support (508) and at least onefenestration (510). When the jaws (502, 504) are advanced out of cannula(512) they are no longer constrained, and thus take the form of theiropen configuration, as shown in FIG. 5B. Opening of the jaws (502, 504)releases ocular device (506) from the engagement mechanism (500). Atleast one tine (514) may be provided in the first jaw (502) and at leastone aperture (516) may be provided in the second jaw (504) to helpsecure a fenestrated ocular device when the jaws are in their closedconfiguration. In FIG. 6, a variation of an engagement mechanism (600)is shown where a first jaw (602) and a second jaw (604) include both atine (606) and an aperture (608) to help grasp a fenestrated oculardevice (610).

Referring to FIGS. 7A-7B, further exemplary engagement mechanisms aredepicted. In FIG. 7A, engagement mechanism (700) comprises complementarymating elements. Specifically, engagement mechanism (700) includes afemale element, notch (702) that is configured to interface with acomplimentary male element (704), shown as a hook-like projection on theocular device (706). Here the notch (702) may be fabricated at the endof a hypodermic tube (708) (which would serve as the positioningelement). Instead of notch (702), the female element of the engagementmechanism (710) may include an opening (712), as shown FIG. 7B, whichinterfaces with male element (704) on the ocular device (706). In FIG.7B, the positioning element (714) may be fabricated from a metal wire orrod and the opening (712) created via laser machining or other processesknown in the art.

In other variations, the engagement mechanism may be configured as shownin FIGS. 8A and 8B. In those figures, engagement mechanism (800)comprises a looped portion (802). It may be beneficial to use thisparticular engagement mechanism with an ocular device (804) including aclasp (806) with arms or tabs (808) having a closed configuration and anexpanded configuration. Similar to the variation shown in FIGS. 5A and5B, tabs (808) are constrained in their closed configuration within thecannula (810) prior to advancement out of the cannula (810). In theirconstrained configuration, tabs (808) engage the looped portion (802) ofthe engagement mechanism (800) to prevent release of the ocular device(804) from the system. When the looped portion (802) of the engagementmechanism (800) is advanced sufficiently so that tabs (808) are nolonger constrained by cannula (810), tabs (808) take on their expandedconfiguration to thus release the ocular device (804) from the loopedportion (802) and into Schlemm's canal, as shown in FIG. 8B.

Another exemplary engagement mechanism (900) is shown in FIG. 9comprising a coiled portion (902) and a hook (904). When an oculardevice (906) having at least one fenestration (908) (e.g., a proximalfenestration) is to be implanted, the hook (904) may be releasablyengaged to the fenestration (908). The ocular device (906) may bedisengaged from the hook by the application of gentle force on the coil(902) or by another component (not shown) that can be advanced over thecoil (902) to push the device (906) off the hook (904). It may beadvantageous to use the hook (904) when retraction of the ocular device(906) is desired.

When the delivery systems are employed to deliver a fluid composition,the fluid composition may be preloaded in a reservoir of the system orloaded into the reservoir prior to use of the system. An exemplarydelivery system for delivering a fluid composition into Schlemm's canalis shown in FIGS. 10A and 10B. Referring to FIG. 10A, delivery system(1000) includes a universal handle (1002) having a grip portion (1004)and a housing (1006). Housing (1006) has a proximal end (1008) and adistal end (1010). A cannula (1012)) is coupled to and extends from thehousing distal end (1010). A drive assembly (1014) is substantiallycontained within the housing (1006) that actuates movement of a slidableconduit (not shown). The cannula (1012) and drive assembly (1014) havethe same configuration as that shown and described in FIGS. 3 and 4A-4Bfor the system tailored for ocular device implantation, and thus are notdescribed in detail here.

The delivery system (1000) also includes a fluid assembly (1016) (shownin FIG. 10B) within the handle (1002) having a loading component (1018)that is configured to allow transfer of a fluid composition from anexternal source into a reservoir defined by the fluid assembly andlinear gear (1020). A slidable conduit (1022) is coaxially disposedwithin the cannula lumen that is in fluid communication with thereservoir. As previously stated, in a tool-based system that does notdeliver an implant or a fluid, the system may not include a reservoir.

In an exemplary method, as illustrated by FIGS. 11A-11C, a fluidcomposition may be transferred into a reservoir (1102) of system (1100)via loading through loading component (1104). As shown in the figures,reservoir (1102) is defined by the fluid assembly (1106) and the lineargear (1108). Linear gear (1108) has a proximal end (1110) and a distalend (1112), and a lumen (1114) extending from the proximal end (1110) tothe distal end (1112). Lumen (1114) is in fluid communication with thelumen (not shown) of the slidable conduit (1118).

To deploy the fluid composition out of the reservoir (1102), linear gear(1108) is retracted in the direction of the arrow (FIG. 11B) so thatreservoir (1102) becomes pressurized. Retraction can be accomplished byrotation of pinion gear mechanisms (1120). Once a sufficient amount ofpressure has been created in the reservoir (1102) the fluid compositioncontained therein is injected through linear gear lumen (1114) andconduit (1118) into Schlemm's canal.

The slidable conduits employed with the systems described herein may beof various configurations. For example, as shown in FIG. 12, the conduit(1200) may be a flexible tube having a lumen in fluid communication withan opening at the distal end (1202). Here, any fluid that is deliveredflows through the distal end (1202) to reach Schlemm's canal. In othervariations, the slidable conduit (1300) may be configured to include aplurality of openings spaced along its axial length. The openings mayhave any suitable shape, e.g., slots (1302) (FIG. 13A) or circles (1304)(FIG. 13B). Fluid compositions delivered using the conduits depicted inFIG. 13A and FIG. 13B may partially flow out of the conduit through theopenings and partially out through the distal end of the conduit. Thedistal end of the conduit may also be configured as a half tube (1306)(FIG. 13C).

II. Methods

Methods for implanting an ocular device and for delivering a fluidcomposition into Schlemm's canal using the systems described above arealso provided. Implant-free methods for providing a force sufficient todisrupt trabeculocanalicular tissues, e.g., by providing a disruptivevolume of viscoelastic fluid or a disruptive tool, are furtherdescribed. The methods are generally single-handed, single-operatorcontrolled methods that are minimally invasive, e.g., they are tailoredfor an ab-interno procedure, which as previously mentioned, can beadvantageous over the more invasive ab-externo approach. However, use ofthe ocular systems in an ab-externo method may be contemplated in someinstances and thus, are not excluded here. The methods for delivering anocular device or fluid, or for providing a disruptive force, may be usedto treat glaucoma, pre-glaucoma, or ocular hypertension. When treatingglaucoma, the methods may also be used in conjunction with a cataractsurgery (before or after) using the same incision.

In general, the methods for implanting an ocular device within Schlemm'scanal first include the step of creating an incision in the ocular wall(e.g., the sclera or cornea) that provides access to the anteriorchamber of the eye. As shown in the stylized depiction of an eye in FIG.14, the cannula (1400) of the ocular delivery system is then advancedthrough the incision and at least partially across the anterior chamber(1402) to the trabecular meshwork (not shown). Schlemm's canal (i.e.,the lumen of Schlemm's canal) (1404) is then accessed with the distalcurved portion of the cannula (1406) and a slidable positioning element,(or, e.g., a slidable tool or guidewire), or slidable conduit(represented generically by element 1408) is advanced from the cannulato implant an ocular device within Schlemm's canal, perform a procedurewithin Schlemm's canal or on any of the neighboring trabeculocanaliculartissues, or deliver a fluid into the canal. However, in some instances,a slidable conduit may not be employed so that any fluid to be deliveredis delivered through the cannula. In yet further variations, just thetrabecular meshwork is punctured and the fluid composition is deliveredwithout circumnavigation of Schlemm's canal.

As previously stated, the cannula may be configured to include aproximal end and a distal curved portion, where the distal curvedportion has a proximal end, a distal end, and a radius of curvaturedefined between the ends. Here the cannula may also include a body and adistal tip having a bevel that directly engages the radius of curvature,e.g., it is contiguous with the radius of curvature. The method may alsoinclude the step of flushing the system with fluid (e.g., to remove airfrom the system) and/or the step of irrigating the operative field toclear away blood or otherwise improve visualization of the field.

Any suitable ocular device that maintains the patency of Schlemm's canalor improves outflow of aqueous humor may be implanted by the systemsdescribed herein. For example, ocular devices that maintain the patencyof Schlemm's canal without substantially interfering with fluid flowacross and along the canal may be implanted. Such devices may comprise asupport having at least one fenestration, as disclosed in U.S. Pat. No.7,909,789, which is incorporated by reference herein in its entirety.Ocular devices that disrupt the juxtacanalicular trabecular meshwork oradjacent inner wall of Schlemm's canal may also be implanted. Inaddition to ocular devices made from metal or metal alloys, the use ofsutures, modified sutures, modified polymers, or solid viscoelasticstructures may be delivered. Fluid compositions such as saline,viscoelastic fluids, air, and gas may also be delivered.

When a fluid composition is delivered into Schlemm's canal, the methodsgenerally include the steps of creating an incision in the ocular wall(e.g., the sclera or cornea) that provides access to the anteriorchamber of the eye; advancing a cannula of the ocular delivery systemthrough the incision and at least partially across the anterior chamberto the trabecular meshwork; accessing Schlemm's canal with the cannula;and delivering the fluid composition into the canal using a conduitslidable within the cannula lumen. The cannula may be configured toinclude a proximal end and a distal curved portion, where the distalcurved portion has a proximal end, a distal end, and a radius ofcurvature defined between the ends. Here the cannula may also include abody and a distal tip having a bevel that directly engages the radius ofcurvature, e.g., it is contiguous with the radius of curvature. Furtheradvantageous cannula features may also be included, which are describedabove. The method may also include the step of flushing the system withfluid (e.g., to remove air from the system) and/or the step ofirrigating the operative field to clear away blood or otherwise improvevisualization of the field.

When an ab-interno method is employed for implanting an ocular device,the method may include the following steps. The surgeon may first viewthe anterior chamber and trabecular meshwork (with underlying Schlemm'scanal) using an operating microscope and a gonioscope or gonioprism.Using a 0.5 mm or greater corneal, limbal, or sclera incision, thesurgeon may then gain access to the anterior chamber. A saline solutionor viscoelastic composition may then be introduced into the anteriorchamber to prevent its collapse. Here the saline solution orviscoelastic composition may be delivered through the delivery systemcannula or by another mode, e.g., by infusion through a sleeve on thecannula. The surgeon, under direct microscopic visualization, may thenadvance the cannula of the delivery system through the incision towardsthe anterior chamber angle. When nearing the angle (and thus thetrabecular meshwork), the surgeon may apply a gonioscope or gonioprismto the cornea to visualize the angle. The application of a viscous fluid(e.g., a viscoelastic composition as previously described) to the corneaand/or gonioscope or gonioprism may help to achieve good opticalcontact. As the surgeon visualizes the trabecular meshwork, the cannulamay then be advanced so that the bevel of at the distal end of thecurved distal portion of the cannula pierces the meshwork and is incommunication with the lumen of Schlemm's canal. The surgeon mayirrigate saline or a viscoelastic composition into the canal or into theanterior chamber to either prevent collapse of chamber, dilate Schlemm'scanal, or wash away any blood that may obscure visualization of cannulaand ocular device delivery. Next, when the ocular device is advanced tothe extent desired by the surgeon, it is released from the engagementmechanism so that it can reside in Schlemm's canal. If repositioning ofthe ocular device is needed or desired, the surgeon may retract and/orreposition the ocular device using the positioning element of thedelivery system. The surgeon may then withdraw the delivery system fromthe eye.

Other variations of the ab-interno method for implanting an oculardevice include the use of an endoscope. Similar to the method above,access to the anterior chamber is first made by incising the cornea,limbus, or sclera. Again, this may be done in combination with cataractsurgery in one sitting, either before or after cataract surgery, orindependently. The anterior chamber may be infused with saline solutionor a viscoelastic composition may be placed in the anterior chamber toprevent its collapse. The saline or viscoelastic may be delivered as aseparate step or it may be infused with the conduit of the deliverysystem, a sleeve on the conduit, or with a separate infusion cannula.The surgeon, under direct microscopic visualization, then advances theendoscope through the incision and towards the angle and trabecularmeshwork. As the surgeon visualizes the trabecular meshwork using theendoscope or any associated video display, the bevel of the cannula isadvanced to pierce the meshwork. The ocular device is then advancedusing the positioning element under endoscopic visualization. Thesurgeon may irrigate saline or a viscoelastic composition into the canalor into the anterior chamber to either prevent collapse of chamber,dilate Schlemm's canal, or wash away any blood that may obscurevisualization of cannula and ocular device delivery. When the oculardevice is advanced to the extent desired by the surgeon, it is releasedfrom the engagement mechanism so that it can reside in Schlemm's canal.If repositioning of the ocular device is needed or desired, the surgeonmay retract and/or advance the ocular device using the positioningelement of the delivery system. The surgeon may then withdraw thedelivery system from the eye.

With respect to the delivery of a fluid composition, the methods aresimilar to the implantation of an ocular device. However, instead ofusing a positioning element, the delivery system employs a slidableconduit to infuse a fluid composition into Schlemm's canal. The surgeonmay first view the anterior chamber and trabecular meshwork (withunderlying Schlemm's canal) using an operating microscope and agonioscope or gonioprism. Using a 0.5 mm or greater corneal, limbal, orsclera incision, the surgeon may then gain access to the anteriorchamber. A saline solution or viscoelastic composition may then beintroduced into the anterior chamber to prevent its collapse. Here thesaline solution or viscoelastic composition may be delivered through thedelivery system cannula or by another mode, e.g., by infusion through asleeve on the cannula. The surgeon, under direct microscopicvisualization, may then advance the cannula of the delivery systemthrough the incision towards the anterior chamber angle. When nearingthe angle (and thus the trabecular meshwork), the surgeon may apply agonioscope or gonioprism to the cornea to visualize the angle. Theapplication of a viscous fluid (e.g., a viscoelastic composition aspreviously described) to the cornea and/or gonioscope or gonioprism mayhelp to achieve good optical contact. As the surgeon visualizes thetrabecular meshwork, the cannula may then be advanced so that the bevelof at the distal end of the curved distal portion of the cannula piercesthe meshwork and is in communication with the lumen of Schlemm's canal.Next, a slidable conduit coaxially disposed within the cannula lumen maybe advanced into the canal under gonioscopic visualization. The slidableconduit may be advanced any suitable amount and direction about thecanal. For example, the slidable conduit may be advanced between about10 degrees to about 360 degrees about the canal, or it may be advancedin two steps, e.g., 180 degrees in a clockwise direction and 180 degreesin a counterclockwise direction about the canal (to thereby achieve afull 360 degree ab-interno viscocanalostomy or canaloplasty). Fluid maybe injected upon advancement or retraction of the conduit. Once theslidable conduit has been positioned within the canal, a fluidcomposition, e.g., a viscoelastic solution, may be continuously orintermittently delivered through the conduit. The fluid composition mayexit the conduit through its distal end (e.g., the through the distaltip), or through openings or fenestrations provided along its shaft, ora combination of both. The openings or fenestrations may be spaced alongthe axial length of the conduit in any suitable manner, e.g.,symmetrically or asymmetrically along its length. Other substances suchas drugs, air, or gas may delivered be in the same manner if desired.

The slidable conduit may be repositioned by retraction or repeatedadvancement and retraction. In some variations of the method, the sameor different incision may be used, but the delivery system cannula isemployed to access and dilate Schlemm's canal from a different direction(e.g., counterclockwise instead of clockwise). Once a sufficient amountof fluid has been delivered, the surgeon may retract the slidableconduit into the cannula and remove the delivery system from the eye. Itshould be understood that these steps may be used alone or incombination with cataract surgery (in one sitting).

Other variations of the ab-interno method for delivering a fluidcomposition include the use of an endoscope. Similar to the methoddescribed directly above, access to the anterior chamber is first madeby incising the cornea, limbus, or sclera. Again, this may be done incombination with cataract surgery in one sitting, either before or aftercataract surgery, or independently. The anterior chamber may be infusedwith saline solution or a viscoelastic composition may be placed in theanterior chamber to prevent its collapse. The saline or viscoelastic maybe delivered as a separate step or it may be infused with the conduit ofthe delivery system, a sleeve on the conduit, or with a separateinfusion cannula. The surgeon, under direct microscopic visualization,then advances the endoscope through the incision and towards the angleand trabecular meshwork. As the surgeon visualizes the trabecularmeshwork via the endoscope or any associated display, the bevel of thecannula is advanced to pierce the meshwork. The slidable conduit is thenadvanced under endoscopic visualization. The slidable conduit may beadvanced any suitable amount and direction about the canal. For example,the slidable conduit may be advanced between about 10 degrees to about360 degrees about the canal, or it may be advanced in two steps, e.g.,180 degrees in a clockwise direction and 180 degrees in acounterclockwise direction about the canal (to thereby achieve a full360 degree ab-interno viscocanalostomy). Once the slidable conduit hasbeen positioned within the canal, a fluid composition, e.g., aviscoelastic fluid, may be continuously or intermittently deliveredthrough the conduit. The fluid composition may exit the conduit throughits distal end (e.g., the through the distal tip), or through openingsor fenestrations provided along its shaft, or a combination of both. Theopenings or fenestrations may be spaced along the axial length of theconduit in any suitable manner, e.g., symmetrically or asymmetricallyalong its length. Other substances such as drugs, air, or gas may bedelivered in the same manner if desired.

The slidable conduit may be repositioned by retraction or repeatedadvancement and retraction. In some variations of the method, the sameor different incision may be used, but the delivery system cannula isemployed to access and dilate Schlemm's canal from a different direction(e.g., counterclockwise instead of clockwise). Once a sufficient amountof fluid has been delivered, the surgeon may retract the slidableconduit into the cannula and remove the delivery system from the eye.

An ab-externo approach to implanting an ocular device or delivering afluid composition may include additional or slightly different steps.For example, the creation of tissue flaps, suturing, etc., may be partof the ab-externo method. In general, the ab-externo method forimplanting an ocular device may include the following steps. First,under microscopic visualization, conjunctiva is incised, a scleral flapis created and tissue is dissected to identify the ostia into Schlemm'scanal. The anterior chamber may be separately infused with saline or mayhave a viscoelastic composition placed in it to prevent collapse of theanterior chamber angle. The operation may be done as a standaloneprocedure or in combination with cataract surgery in one sitting. It mayalso be done before the cataract surgery portion or after it.

Using the delivery system described herein, the cannula may be advancedinto Schlemm's canal and the ocular device advanced using thepositioning element under direct microscopic visualization or through agonioscope or gonioprism. When the ocular device is advanced the desiredamount, the surgeon may release the ocular device from the positioningelement by actuating the engagement mechanism and remove the deliverysystem from the eye and operating field. The scleral wound is thenclosed, using for example, sutures or tissue adhesive. If repositioningof the ocular device is needed or desired, the surgeon may retractand/or advance the ocular device using the positioning element of thedelivery system.

With respect to the delivery of a fluid composition, the ab-externomethod is similar to ab-interno delivery. However, instead of using apositioning element, the delivery system employs a slidable conduit toinfuse a fluid composition into Schlemm's canal. First, undermicroscopic visualization, conjunctiva is incised, a scleral flap iscreated and tissue is dissected to identify the ostia into Schlemm'scanal. The anterior chamber may be separately infused with saline or mayhave a viscoelastic composition placed in it to prevent collapse of theanterior chamber angle. The operation may be done as a standaloneprocedure or in combination with cataract surgery in one sitting. It mayalso be done before the cataract surgery portion or after it.

Using the delivery system described herein, the cannula may be advancedinto Schlemm's canal and a slidable conduit coaxially disposed withinthe cannula lumen may be advanced into the canal under gonioscopicvisualization. Once the slidable conduit has been positioned within thecanal, a fluid composition, e.g., a viscoelastic fluid, may becontinuously or intermittently delivered through the conduit. The fluidcomposition may exit the conduit through its distal end (e.g., thethrough the distal tip), or through openings or fenestrations providedalong its shaft, or a combination of both. The openings or fenestrationsmay be spaced along the axial length of the conduit in any suitablemanner, e.g., symmetrically or asymmetrically along its length. Othersubstances such as drugs, air, or gas may delivered be in the samemanner if desired. The slidable conduit may be repositioned byretraction or repeated advancement and retraction. The delivery systemmay then be removed from the eye.

The fluid compositions may be delivered in a manner where retraction ofa system component allows advancement of the fluid out of the systemcannula. Referring again to FIGS. 11A-11C, linear gear (1108) isretracted in the direction of the arrow (FIG. 11B) so that reservoir(1102) becomes pressurized. Retraction can be accomplished by rotationof pinion gear mechanisms (1120). Once a sufficient amount of pressurehas been created in the reservoir (1102) the fluid composition containedtherein is injected through linear gear lumen (1114) and conduit (1118)into Schlemm's canal. It should be understood that the ocular deliverysystems may be configured so that the fluid compositions are deliveredcontinuously, passively, automatically, or actively by the surgeon. Thefluid compositions may also be delivered to the canal independent of thegear shaft movement with a pump or auxiliary plunger.

The fluid compositions that may be delivered by the ocular systemsdescribed herein include saline and viscoelastic fluids. Theviscoelastic fluids may comprise hyaluronic acid, chondroitin sulfate,cellulose, derivatives or mixtures thereof, or solutions thereof. In onevariation, the viscoelastic fluid comprises sodium hyaluronate. Inanother variation, the viscoelastic composition may further include adrug. For example, the viscoelastic composition may include a drugsuitable for treating glaucoma, reducing or lowering intraocularpressure, reducing inflammation or scarring, and/or preventinginfection. The viscoelastic composition may also include agents that aidwith visualization of the viscoelastic composition. For example, dyessuch as but not limited to fluorescein, trypan blue, or indocyaninegreen may be included. In some variations, a fluorescent compound orbioluminescent compound is included in the viscoelastic composition tohelp with its visualization. In other variations, the system deliversthe drug alone, without the viscoelastic composition. In this case, thedrug may be loaded onto or into a sustained release biodegradablepolymer that elutes drug over a period of weeks, months, or years. It isalso contemplated that air or a gas could be delivered with the systems.

The fluid compositions may be delivered to dilate Schlemm's canal. Theentire length of Schlemm's canal or a portion thereof may be dilated bythe fluid. For example, at least 75%, at least 50%, at least 25%, or atleast 10% of the canal may be dilated. The fluid compositions may alsobe delivered to treat various medical conditions, including but notlimited to, glaucoma, pre-glaucoma, and ocular hypertension.

Additionally, the fluid compositions may be delivered to restore thetubular anatomy of Schlemm's canal, to clear obstructions within thecanal, to disrupt juxtacanalicular trabecular meshwork or the inner wallof Schlemm's canal within the canal, or to expand the canal. Here thedelivery systems may include wires, tubes, balloons, instruments thatdeliver energy to the tissues, and/or other features to help with thesemethods. It is contemplated that glaucoma may be treated using suchsystems with additional features. The surface of these systems may alsobe roughened or have projections to further disrupt the inner wall ofSchlemm's canal and juxtacanalicular trabecular meshwork to enhanceaqueous humor outflow or permeability.

When the systems and devices are tailored to provide a disruptive forceto the trabeculocanalicular tissues, implant-free methods may beemployed, e.g., by delivering a disruptive volume of viscoelastic fluid,advancing disruptive tools, e.g., cannulas, conduits, catheters, etc.,including one or more disruptive components on their distal portions, orboth. Exemplary disruptive components include, without limitation,notches, hooks, barbs, or combinations thereof. Depending on factorssuch as the type or severity of the condition being treated, thedisruptive force may be generated to partially or completely destroyand/or remove the trabecular meshwork, and may be adjusted by varyingthe volume of viscoelastic fluid delivered, or by varying the toolconfiguration. Exemplary volumes of viscoelastic fluid that may besufficient to provide a disruptive force may range from about 1 μl toabout 50 μl, from about 1 μl to about 30 μl, or from about 2 μl to about16 μl. In one variation, a volume of about 4 μl is sufficient to disruptSchlemm's canal and/or the surrounding tissues. In other variations, thevolume of viscoelastic fluid sufficient to disrupt trabeculocanaliculartissues may be about 2 μl, about 3 μl, about 4 μl, about 5 μl, about 6μl, about 7 μl, about 8 μl, about 9 μl, about 10 μl, about 11 μl, about12 μl, 13 μl, about 14 μl, about 15 μl, about 16 μl, about 17 μl, about18 μl, about 19 μl, about 20 μl, about 25 μl, about 30 μl, about 35 μl,about 40 μl, about 45 μl, or about 50 μl. The total volume ofviscoelastic fluid may be delivered along a 360 degree arc (1600) ofSchlemm's canal during a single advancement from a single access point(1602) in the canal (e.g., as shown in FIG. 16) or withdrawal of theconduit (1604), or along lesser degrees of arc in multiple advancementsor withdrawals of the conduit. For example, as shown in FIG. 17, aconduit (1700) may be advanced along a 180 degree arc of the canal inboth clockwise (1702) and counterclockwise (1704) directions to deliverfluid from, e.g., a single access point (1706) in the canal. Referringto FIGS. 16 and 17, an exemplary disruptive volume of, 4 μl may bedelivered along a 360 degree arc of the canal while the conduit isadvanced from a single access point in the canal, or 2 μl may bedelivered along a 180 degree arc of the canal during two advancements(one in the clockwise direction and the other in the counterclockwisedirection) of the conduit from a single access point in the canal. Theconduit may access the canal from a single point or from multiplepoints. The amount or degree of tissue disruption may be varied by thevolume of fluid delivered. For example, 8 μl may be used to perforate orgently tear the meshwork, while 16 μl may be used to maximally tear themeshwork. More specifically, about 1 to 2 μl may be used to dilateSchlemm's canal and collector channels; about 2 to 4 μl may be used todilate Schlemm's canal and collector channels, and disrupt/stretchjuxtacanalicular tissues; and about 4 to 6 μl may be used for all theforegoing and for the creation of microtears in the trabecular meshworkand juxtacanalicular tissues (further increasing porosity and outflow).A volume of about 8 to 16 μl may be used for all the foregoing and forsubstantial perforation/tearing of the trabecular meshwork andjuxtacanalicular tissues. A volume of about 16 to 50 μl may be used forsubstantial or complete tearing of the trabecular meshwork. When fluidsare not used, and only a disruptive tool is employed, the outer diameterof the conduit or tool may be variously sized for disruption of tissues,analogous to how fluid volumes may be varied to vary the level ofdisruption. For example, a conduit or tool having an outer diameterranging from about 50 to about 100 microns may be advanced through thecanal to slightly dilate the canal and break or remove septaeobstructing circumferential canalicular flow. A conduit or tool havingan outer diameter ranging from about 100 to 200 microns may be employedto perform the foregoing, and may also to begin to stretch thetrabecular meshwork and juxtacanalicular tissues. A conduit or toolhaving an outer diameter ranging from about 200 to about 300 microns maybe able to perform the above, but may also create microtears in thetrabecular meshwork and juxtacanalicular tissues, and may maximallydilate the collector channels. A conduit or tool having an outerdiameter ranging from about 300 to about 500 microns may maximallydisrupt the tissues and may create tears or perforations all along thetrabecular meshwork and juxtacanalicular tissues. Additionally, thefurther the advancement of the conduit or tool through the canal, thegreater the efficacy of the procedure. For example, the conduit or toolmay be advanced out from the tip of the cannula and into the canal abouta 30 degree arc of the canal (e.g., advanced about 3 to 4 mm out of thecannula), advanced about a 60 degree arc of the canal (e.g., advancedabout 6 to 8 mm out of the cannula), advanced about a 90 degree arc ofthe canal (e.g., advanced about 10 mm out of the cannula), advancedabout a 120 arc of the canal (e.g., advanced about 15 mm out of thecannula), advanced about a 180 degree arc of the canal (e.g., advancedabout 20 mm out of the cannula), or advanced about a full 360 degrees ofthe canal (e.g., advanced about 36 to 40 mm out of the cannula), formaximal efficacy and maximal intraocular pressure reduction.

The implant-free methods for treating conditions of the eye may includeadvancing a conduit into Schlemm's canal, where the conduit has beenloaded with a volume of viscoelastic fluid, and delivering theviscoelastic fluid into Schlemm's canal at a volume sufficient todisrupt the trabeculocanalicular tissues to reduce intraocular pressure.However, the implant-free methods for treating conditions of the eye maynot necessarily include delivery of viscoelastic fluids. In theseinstances, the method may comprise advancing a device into Schlemm'scanal, where the device has a diameter between about 300 and about 500microns, or about 150 and about 200 microns, and where advancement ofthe device into Schlemm's canal disrupts the canal and/ortrabeculocanalicular tissues in a manner sufficient to reduceintraocular pressure.

Other methods for treating conditions of the eye may be single-handed,single-operator methods for introducing viscoeleastic fluid intoSchlemm's canal that include advancing a conduit into Schlemm's canal,where the conduit has been loaded with a volume of viscoelastic fluid,and delivering the viscoelastic fluid into Schlemm's canal, wheredelivering the volume of viscoelastic fluid is accomplished by asingle-handed device used by a single operator.

Again, when viscoelastic fluids are delivered in the methods disclosedherein, the disruptive volume may be between about 2 μl to about 8 μl.It may be beneficial to deliver a volume of about 4 μl of viscoelasticfluid in certain instances. The viscoelastic fluid may be deliveredwhile advancing the conduit of a single-handed, single-operatorcontrolled device from Schlemm's canal in the clockwise direction,counterclockwise direction, or both, or during withdrawal of the conduitfrom Schlemm's canal. As previously stated, the viscoelastic fluid maybe delivered to disrupt Schlemm's canal and surroundingtrabeculocanalicular tissues. For example, the delivered viscoelasticfluid may cause disruption by dilating Schlemm's canal, increasing theporosity of the trabecular meshwork, stretching the trabecular meshwork,forming microtears in juxtacanalicular tissue, removing septae fromSchlemm's canal, dilating collector channels, or a combination thereof.The conduit may be loaded with the viscoelastic fluid at the start of anocular procedure so that the fluid can be delivered by a single device.This is in contrast to other systems that use forceps or otheradvancement tool to advance a fluid delivery catheter into Schlemm'scanal and/or devices containing viscoelastic fluid that are separate orindependent from a delivery catheter or catheter advancement tool, andwhich require connection to the delivery catheter or catheteradvancement tool during a procedure by an assistant while the deliverycatheter or catheter advancement tool is held by the surgeon.

In some variations, the methods disclosed herein may include advancementof the conduit (or a tool) about a 360 degree arc of Schlemm's canal,about a 270 degree arc of Schlemm's canal, about a 120 degree arc ofSchlemm's canal, about a 180 degree arc of Schlemm's canal, or about a90 degree arc of Schlemm's canal. In yet further variations, advancementof the conduit (or a tool) may be about a 0 to 5 degree arc of Schlemm'scanal, about a 30 degree arc of Schlemm's canal, or about a 60 degreearc of Schlemm's canal. Advancement may occur from a single access pointin Schlemm's canal or from multiple access points in the canal. When adisruptive force is to be provided, it may be beneficial to advance theconduit in both clockwise and counterclockwise directions about a 180degree arc of Schlemm's canal from a single access point in the canal.

Prior to the introduction of goniotomy and trabeculotomy (both of whichare typically used to treat an obstructed trabecular meshwork, oftengenetically-driven at a young age), congenital glaucoma uniformlyresulted in blindness. Despite the invasiveness of goniotomy (which isperformed ab-interno, but a sharp scalpel is used to cut 30-60 degreesof meshwork to improve outflow) and trabeculotomy (ab-externo methodwhere deep scleral incisions unroof Schlemm's canal and the meshwork iscut with a probe), the procedures are viewed as being effective and haveallowed many pediatric patients to avoid an entire lifetime ofblindness. In 1960, Burian and Smith each independently describedtrabeculotomy ab-externo. In this highly invasive ab-externo operation,the surgeon makes a deep scleral incision, finds Schlemm's canal,cannulates all 360 degrees of Schlemm's canal externally with a catheteror specially designed probe called a trabeculotome, and finally tensionsboth ends of the catheter or probe to the point where the trabeculotomecuts through the entire trabecular meshwork into the anterior chamber toimprove drainage.

More recent attempts at decreasing the invasiveness of ab-externotrabeculotomy have been developed by NeoMedix, which commercializes adevice called “Trabectome”. The Trabectome attempts to maketrabeculotomy easier by using an ab-interno approach. The instrument andmethods involve removal of the trabecular meshwork ab interno byelectrocautery using an instrument that also provides infusion andaspiration. The disadvantages of the Trabectome are three-fold: 1) thedevice employs an energy-based mechanism to ablate trabecular meshwork,which is believed to cause inflammation and scarring in the eye, whichin turn can adversely impact outflow and pressure; 2) thedevice/procedure is ergonomically limited—it requires a foot pedal andpower cords to activate electrocautery and irrigation in addition tobeing limited to 60-120 degrees of meshwork therapy per corneal orscleral entry incision; and 3) Because it involves energy-based ablationand irrigation, there is a significant capital equipment cost that maylimit adoption.

The methods (as well as systems and devices) described herein, includingthe method for providing a disruptive force to trabeculocanaliculartissues, may be highly suitable for ab-interno trabeculotomy andgoniotomy given that they avoid the use of electrocautery, and arecapable of advancing conduits over larger degrees of arc of Schlemm'scanal. In some variations of the ab-interno trabeculotomy and goniotomymethods, the procedure includes advancing a cannula at least partiallythrough the anterior chamber of the eye, entering Schlemm's canal at asingle access point using the cannula, and delivering a volume of aviscoelastic fluid through a conduit slidable within, and extendablefrom, the cannula, sufficient to disrupt the structure of Schlemm'scanal and surrounding tissues to reduce intraocular pressure. Othermethods that may be useful in treating conditions of the eye include thesteps of entering Schlemm's canal using a conduit extendable from asingle-operator controlled handle, the handle comprising a fluidreservoir, and delivering a volume of a viscoelastic fluid from thefluid reservoir through the conduit by increasing pressure within thefluid reservoir, where the volume of delivered viscoelastic fluid issufficient to disrupt the structure of Schlemm's canal and surroundingtissues to reduce intraocular pressure. The disruptive volume may bebetween about 2 μl to about 16 μl. In one variation, the disruptivevolume is about 4 μl of viscoelastic fluid. As previously stated, insome instances the disruptive volume may range anywhere between about 20μl to about 50 μl.

More specifically, disruption (e.g., cutting, destruction, removal,etc.) of the trabecular meshwork may be accomplished by removing thecannula from the eye while leaving the conduit in the canal, therebytearing through the meshwork. Alternatively, tissue disruption may occurby visco-dilating excessively and intentionally with at least about 1μl, at least about 2 μl, at least about 3 μl, at least about 4 μl, atleast about 5 μl, at least about 6 μl, at least about 7 μl, at leastabout 8 μl, at least about 9 μl, at least about 10 μl, at least about 11μl, at least about 12 μl, at least about 13 μl, at least about 14 μl, atleast about 15 μl, at least about 16 μl, at least about 17 μl, at leastabout 18 μl, at least about 19 μl, or at least about 20 μl ofviscoelastic fluid per 360 degree arc of the canal. The amount or degreeof tissue disruption may be varied by the volume of fluid delivered. Forexample, 8 μl may be used to perforate or gently tear the meshwork,while 16 μl may be used to maximally tear the meshwork. In somevariations, at least about 20 μl, at least about 25 μl, at least about30 μl, at least about 35 μl, at least about 40 μl, at least about 45 μl,or at least about 50 μl of viscoelastic fluid may be delivered.

Another method for disrupting tissues may include using oversizedconduits (e.g., having an outside diameter of 300-500 microns) to tearthe meshwork upon delivery, or inflating or expanding the conduit onceit has been fully advanced into Schlemm's canal to stretch, disrupt,rupture, or fully tear the meshwork. For example, a catheter/conduit,probe, or wire (with or without a lumen) whose tip is 200-250 microns inouter diameter, but having a shaft that begins to flare outwards after 3clock hours of Schlemm's canal (i.e., at about the 5 or 10 mm mark onthe catheter/conduit) up to about 300, up to about 400, or up to about500 microns, may be used, so that as the tip advances comfortably withinSchlemm's canal, the enlarged shaft trails behind and ruptures thetrabecular meshwork as it is advanced.

In yet further methods, tissue disruption may be accomplished by theab-interno delivery of a suture throughout Schlemm's canal, which isthen sufficiently tensioned to stretch the canal, disrupt the trabecularmeshwork, and/or tear through the meshwork (“Ab interno SutureTrabeculotomy”). Here a tool including a grasping element may beemployed for pulling the distal suture tip inwards as the cannula isbeing withdrawn from the eye, severing all 360 degrees or a segment ofthe trabecular meshwork, or for tying the suture ends together toprovide tension on the meshwork without necessarily tearing it.

Customizing a body segment of the conduit proximal to the tip with anotch or notches or barbs that catch the meshwork as the distal tip isbeing guided and advanced along Schlemm's canal could also be used,thereby disrupting, partially tearing, fully tearing, and/or removingtrabecular meshwork upon advancement. Additionally, an implant withedges specifically designed to cut the meshwork could be used. Stillother methods for disrupting tissues may involve customizing the system(e.g., the conduit, any catheters or wires, probe tips, etc.) to catchor grasp the meshwork upon retraction after complete advancement throughthe canal. This may be done using a wire with a bent tip, hook, notch,or barb on its end that is advanced through the lumen of the catheterthat then snags the meshwork upon retraction, tearing it along itslength or removing it altogether, or solely with a metal or polymer wireor suture (no catheter) whose tip (and/or body) is hooked, notched, orbarbed in such a way that it can be advanced into Schlemm's canalwithout tearing the meshwork but snags the meshwork upon retraction,tearing the meshwork and/or removing it completely. Referring to FIG.18A, a cannula (1800) may be inserted into the anterior chamber (1802)and Schlemm's canal (1804), and a tool (e.g., a slidable conduit (1806))may be advanced within the canal (1804). As shown in FIG. 18B, theslidable conduit (1806) can be retracted and withdrawn from the anteriorchamber (1802) without retracting the cannula (1800). This action byitself may tear the trabecular meshwork. Alternatively, as shown in FIG.18C, the conduit (1806) may be provided with a disruptive tool, e.g., asharp-edged element (1808), that can cut or tear the trabecular meshworkwhile being retracted into the cannula (1800), which is held stationary.Exemplary sharp-edged elements may be a hook, wire, or any othersuitable shape memory component that can extend from the cannula totear, cut, or remove trabecular meshwork.

The configuration of the ocular delivery system may be advantageous inmany different respects. In one aspect, the delivery system is capableof being used in an ab-interno method of implanting an ocular device inSchlemm's canal or an ab-interno method of delivering a fluidcomposition or a tool into the canal. In another aspect, the deliverysystem cannula is configured to allow easy and atraumatic access toSchlemm's canal. Furthermore, the delivery system is configured in amanner that gives the surgeon greater freedom of use, all in a singleinstrument. For example, the handle of the system is configured so thatit can be used with either the right or left hand on either the right orleft eye just by flipping over the handle or rotating the cannula.Furthermore, the delivery system is designed so that it is capable ofbeing used with the right hand to access Schlemm's canal in acounterclockwise fashion, use with the left hand to access to Schlemm'scanal in a clockwise fashion, or use with the left hand to access thecanal in a counterclockwise fashion, etc. Thus, access to the canal fromall four quadrants of the eye can be achieved. In yet a further respect,the delivery system comprises single-handed, single-operator controlleddevices configured to provide a force sufficient to disrupt Schlemm'scanal and surrounding tissues to improve flow through thetrabeculocanalicular outflow pathway. The systems generally combineaccess cannulas, delivery conduits, conduit advancement mechanisms,disruptive tools, and viscoelastic fluids into a single device so thatone person or one hand can advance the conduit or tool, or deliver thefluid.

1. A method for delivering fluids using a device comprising a cannula, aconduit slidably disposed within, and advanceable distally from, thecannula, and a handle coupled to the cannula, wherein a portion of thehandle defines a fluid reservoir, comprising: operating the handle witha single hand to deliver the fluid from the reservoir through theconduit.